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Modulation of Bacterial Quorum Sensing with Synthetic Ligands

a technology of quorum sensing and synthetic ligands, which is applied in the direction of biocide, heterocyclic compound active ingredients, drug compositions, etc., can solve the problems of inability to selectivise these ligands for different r proteins, scarce potent antagonists, and inability to design new ligands

Active Publication Date: 2008-12-18
WISCONSIN ALUMNI RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]The present invention provides compounds and methods for modulation of quorum sensing of bacteria. In an embodiment, the compounds of the present invention are able to act as replacements for naturally occurring bacterial quorum sensing ligands in a ligand-protein binding system; that is, they imitate the effect of natural ligands and produce an agonistic effect. In another embodiment, the compounds of the present invention are able to act in a manner which disturbs or inhibits the naturally occurring ligand-protein binding system in quorum sensing bacteria; that is, they produce an antagonistic effect.
[0021]In an embodiment, the methods of the present invention can be used for disrupting a biofilm formed by a quorum sensing bacterium. A method of the present invention for disrupting a biofilm comprises contacting the biofilm with an effective amount of a compound of the present invention. In an embodiment, the methods of the present invention can be used to diminish or inhibit biofilm production. Alternatively, the methods of the present invention can be used for causing a quorum sensing bacterium to initiate or enhance biofilm production.
[0023]In another embodiment of the methods, the compounds of the present invention can be administered to a subject to initiate an immune response. In an embodiment, the administration of an effective amount of a compound of the present invention to a subject can initiate or enhance the symbiotic behavior of quorum sensing bacteria in the subject. In an embodiment, the administration of an effective amount of a compound of the present invention to a subject can disrupt a biofilm of quorum sensing bacteria in the subject. In an embodiment, the administration of an effective amount of a compound of the present invention to a subject can initiate or enhance the symbiotic behavior of a target species or a selected strain of a target species of quorum sensing bacteria in the subject. In an embodiment, the administration of an effective amount of a compound of the present invention to a subject can regulate the virulence of quorum sensing bacteria in the subject. In an embodiment, the administration of an effective amount of a compound of the present invention to a subject can regulate the virulence of a target species or a selected strain of a target species of quorum sensing bacteria in the subject.
[0025]The methods of the present invention also provide for regulation of the virulence, biofilm production, or symbiotic behavior of a quorum sensing bacteria by contacting the bacteria with a photoactive compound and illuminating the bacteria and photoactive compound. In an embodiment, illuminating a photoactive compound of the present invention can change the agonistic or antagonistic behavior of the compound.

Problems solved by technology

However, potent antagonists remain scarce.
Further, as most non-native AHLs have only been tested against one bacterial species, the selectivities of these ligands for different R proteins are largely unknown.
Insufficient structure-activity relationship (SAR) data for non-native AHLs within and between different Gram-negative bacteria has precluded the design of new ligands with improved activities against and selectivities for R proteins.
Likewise, this dearth of SAR data has also protracted the design of non-native AHL activators of QS.
The use of different assay procedures to assess agonistic or antagonistic activity against the same R protein has further complicated comparisons between past studies.

Method used

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  • Modulation of Bacterial Quorum Sensing with Synthetic Ligands
  • Modulation of Bacterial Quorum Sensing with Synthetic Ligands
  • Modulation of Bacterial Quorum Sensing with Synthetic Ligands

Examples

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Comparison scheme
Effect test

example 1

From Antagonist to Super-Agonist

Structural Isomers of N-Phenylacetanoyl-L-Homoserine Lactones Elicit Strong and Opposite Quorum Sensing Responses in Vibrio fischeri

[0169]Abstract: Bacteria monitor their population densities using low molecular weight ligands in a process known as quorum sensing. At sufficient cell densities, bacteria can change their mode of growth and behave as multicellular communities that play critical roles in both beneficial symbioses and in the pathogenesis of infectious disease. The development of non-native ligands that can block quorum-sensing signals has emerged as a promising new strategy to attenuate these divergent outcomes. Here, we report that N-phenylacetanoyl-L-homoserine lactones are capable of either inhibiting or, in some cases, strongly inducing quorum sensing in the bacterial symbiont Vibrio fischeri. Moreover, simple structural modifications to these ligands have remarkable effects on activity. For example, movement of a single substituent o...

example 2

Small Molecule Modulation of Quorum Sensing Revealed by the Systematic Evaluation of Synthetic Ligands Across Three Gram-Negative Bacterial Species

[0206]Abstract: Bacteria monitor their population densities using low molecular weight ligands in a phenomenon called quorum sensing. At high cell densities, bacteria use this chemical signaling process to change their mode of growth and behave as multicellular communities that play essential roles both in the pathogenesis of infectious disease and in beneficial symbioses. There is intense and growing interest in the development of synthetic ligands that can intercept quorum sensing signals and attenuate these divergent outcomes. Both broad spectrum and species specific modulators of quorum sensing hold significant value as small molecule tools for fundamental studies of this complex cell-cell signaling process and for future biocontrol applications. However, synthetic inhibitors or activators of quorum sensing in one species, let alone m...

— example 2

REFERENCES AND NOTES—EXAMPLE 2

[0284]Bassler, B. L.; Losick, R. Cell 2006, 125, 237-246.[0285]Waters, C. M.; Bassler, B. L. Ann. Rev. Cell Dev. Biol. 2005, 21, 319-346.[0286]Fuqua, C.; Parsek, M. R.; Greenberg, E. P. Annu. Rev. Genet. 2001, 35, 439[0287]de Kievit, T. R.; Iglewski, B. H. Infect. Immun. 2000, 68, 4839-4849.[0288]Hall-Stoodley, L.; Costerton, J. W.; Stoodley, P. Nat. Rev. Microbiol. 2004, 2, 95-108.[0289]Winans, S. C. Trends Microbiol. 1998, 6, 382-383.[0290]Greenberg, E. P., Quorum Sensing in Gram-Negative Bacteria: An Important Signaling Mechanism in Symbiosis and Disease. In Microbial Ecology and Infectious Disease, Rosenberg, E., Ed. American Society for Microbiology: Washington, D.C., 1999; pp 112-122.[0291]Ruby, E. G. Annu. Rev. Microbiol. 1996, 50, 591-624.[0292]Lyon, G. J.; Muir, T. W. Chem. Biol. 2003, 10, 1007-1021.[0293]Gonzalez, J. E.; Keshavan, N. D. Microbiol. Mol. Biol. Rev. 2006, 70, 859-875.[0294]Fuqua, C.; Greenberg, E. P. Nat. Rev. Mol. Cell. Biol. 20...

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Abstract

The present invention provides compounds and methods for modulation of the quorum sensing of bacteria. In an embodiment, the compounds of the present invention are able to act as replacements for naturally occurring bacterial quorum sensing ligands in a ligand-protein binding system; that is, they imitate the effect of natural ligands and produce an agonistic effect. In another embodiment, the compounds of the present invention are able to act in a manner which disturbs or inhibits the naturally occurring ligand-protein binding system in quorum sensing bacteria; that is, they produce an antagonistic effect. The compounds of the present invention comprise N-acylated-homoserine lactones (AHLs) comprised of a wide range of acyl groups.

Description

CROSS REFERENCE TO RELATED APPLICATION[0001]This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Nos. 60 / 895,598, 60 / 912,345, and 60 / 974,026 filed on Mar. 19, 2007, Apr. 17, 2007, and Sep. 20, 2007, respectively, each of which is hereby incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with U.S. government support under Award No. AI063326 awarded by the National Institutes of Health. The U.S. government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Many microbial pathogens cause tremendous damage worldwide, in humans as well as in animals and crop plants. The continuing emergence of multiple-drug-resistant pathogen strains has necessitated finding new compounds that can be used in antimicrobial treatment. In general, two strategies exist for controlling pathogens, either kill the pathogen or attenuate its virulence such that it does ...

Claims

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Application Information

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IPC IPC(8): A61K31/365C12N1/20C40B40/04A61P31/00C07D307/33
CPCA61K31/365C07D307/32C07D309/30C07D333/32C07D405/12C12N1/36C07D409/12C07D413/12C07D417/12C07D307/33C07D407/12A61P31/00Y02A50/30
Inventor BLACKWELL, HELEN E.GESKE, GRANT D.O'NEILL, JENNIFER C.
Owner WISCONSIN ALUMNI RES FOUND
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